Dental composition

ABSTRACT

Dentifrices containing cationic antibacterial agents are disclosed herein.

BACKGROUND OF THE INVENTION

The present invention relates to a dentifrice comprising a cationicantibacterial agent useful in the prophylaxis and/or treatment ofperiodontal disease, calculus and caries and selected abrasives. A newthickening agent comprising a soluble alkali metal pyrophosphate and acalcium salt is also disclosed.

The use of antibacterial agents, including cationic antibacterialagents, in oral hygiene compositions has been widely advocated as ameans of reducing the bacterial plaque population and this may bebeneficial in the treatment of periodontal disease, calculus and/orcaries.

While mouthwashes containing cationic antibacterial agents areavailable, these suffer the disadvantage that the cationic antibacterialagents tend to leave a brown stain due to interaction of the agents withplaque. Such a drawback may be, in principle, minimized by using theantibacterial agent in a dentifrice, so that the abrasive includedtherein removes the stained plaque. In practice however there are foundto be severe problems in providing a useful formulation because of theintrinsic incompatibility of the cationic antibacterial agents with manyof the other conventional elements of a dentifrice formulation, whichincompatibility drastically reduces the bio-availability of the cationicagent. In addition, the cationic antibacterial agents often have abitter taste which needs to be masked to provide a product which isacceptable to the consumer.

It has now been discovered that the problem of bio-availability may beovercome or at least mitigated by the use of certain abrasives incombination with cationic antibacterial agents in dentifrices. Also, thethickening agents based on a pyrophosphate and a calcium salt make itpossible to eliminate all or essentially all of certain thickeningagents such as non-abrasive silica gels which may reduce CPCavailability.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a dentifrice for reducingplaque formation and treating gingivitis on teeth and soft tissuecomprising:

(a) an amount of a cationic antibacterial agent sufficient to usefullyreduce plaque formation and treat gingivitis;

(b) at least one thickening agent which is not an anionic thickeningagent;

(c) at least one surfactant which is not an anionic surfactant; and

(d) a non-silica abrasive which is essentially insoluble in saiddentifrice.

Another aspect of this invention is that it has been found these andother dentifrice can be thickened by combining a soluble or sparinglysoluble alkali metal pyrophosphate with an insoluble or essentiallyinsoluble calcium salt thereby creating in situ material which thickensdentifrice formulations.

Optionally a humectant, an anti-caries agent, flavoring agents and otherexcipients necessary or useful in formulating and using a dentifrice canbe included in these compositions.

SPECIFIC EMBODIMENTS

These dentifrice may be substantially solid, pasty or liquid incharacter such as is found in a tooth powder, a dental tablet or atoothpaste or dental cream. These compositions typically will have a pHsimilar to that of the oral cavity, but may be formulated so as to beeither acidic or alkaline. Buffers may be added to maintain pH ifdesired.

Suitable cationic antibacterial agents for use in dentifrices of theinvention include:

(i) quaternary ammonium compounds, for instance those in which one ortwo of the substituents on the quaternary nitrogen has between 8 and 20,preferably 10 and 18 carbon atoms and is preferably an alkyl group,which may optionally be interrupted by an amide, ester, oxygen, sulphur,or heterocyclic ring. The remaining nitrogen substituents will have alower number of carbon atoms, for instance between 1 and 7, and arepreferably alkyl, for instance methyl or ethyl, or benzyl. The anionwill be an orally acceptable salt forming group. Examples of suchcompounds including benzalkonium, chloride, dodecyl trimethyl ammoniumchloride, benzyl dimethyl stearyl ammonium chloride, and cetyl trimethylammonium bromide, benzethonium chloride (diisobutyl phenoxyethoxyethyldimethylbenzyl ammonium chloride), and methyl benzethonium chloride;

ii) pyridinium and isoquinolinium compounds, exemplified byhexadecylpyridinium chloride, cetyl pyridinium chloride, and alkylisoquinolinium bromide;

(iii) pyrimidine derivatives such as hexetidine (5-amino-1,3-bis(2-ethylhexyl)-5-methylhexahydropyrimidine);

(IV) amidine derivatives such as hexamidine isethionate(4,4'-diamidino-α,ω-diphenoxyhexane isothionate);

(v) bispyridine derivatives such as octenidine(N,N'[1,10-decanediyldi-1(4H)-pyridinyl-4-ylidene]bis(1-octanaminedihydrochloride); and

(vi) biguanides including:

(a) mono-biguanides such as p-chlorobenzyl biguanide, andN'-(4-chlorobenzyl)-N"-(2,4-dichlorobenzyl)biguanide.

(b) bis-biguanides of the general formula (I): ##STR1## wherein: A₁ andA₂ are independently a phenyl group optionally substituted by(C₁₋₄)alkyl, (C₁₋₄)alkoxy, nitro, halogen, C₁₋₁₂)alkyl group, or(C₄₋₁₂)alicylclic;

X₁ and X₂ are independently (C₁₋₃)alkylene;

R and R¹ are independently hydrogen, (C₁₋₁₂)alkyl, or aryl(C₁₋₆)alkyl;

Z₁ and Z₂ are independently 0 or 1;

Q is CH₂, oxygen, sulfur, or aryl;

n in each (CH₂)n group is independently is an integer from 1 to 12 butthe total of both n groups may not exceed 12;

aryl is phenyl, naphthyl or another aromatic ring; and orally acceptableacid addition salts thereof.

Preferred compounds are chlorhexidine and alexidine.

(c) poly(biguanides) such as polyhexamethylene biguanide hydrochloride.

An amount sufficient of the cationic antibacterial agent to usefullyreduce plaque formation and treat gingivitis will be one in the range ofabout 0.005 to 10% weight/weight (w/w), preferably 0.005 to 5%, morepreferably 0.005 to 2.5% and most preferably 1.0% w/w.

Any thickening agent may be used so long as it is not an anionicthickening agent. More specifically, nonionic and cationic thickeningagents are preferred for use in this invention.

Suitable nonionic thickening agents include (C₂₋₆)alkylene oxidemodified (C₁₋₆)alkylcellulose ethers, for instancehydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, and mixtures thereof.

Suitable cationic thickening agents include quaternary cellulosederivatives such as the products supplied by Amerchol Europe under thetrademark LR 30M and JR 30M, cationic guar gum derivatives such as theproducts supplied by Celanse under the trademark Jaguar C17 (guarhydroxypropyltriammonium chloride), or a copolymer of a diallyl ammoniumchloride and acrylic acid such as the product supplied by Merck and Co.under the trademark `Merquat 280` (CFTA approved name polyquaterinium22). Other thickening agents which may be employed includepolyvinylpyrrolidone, starch and certain non-abrasive silica gels suchas those sold by Huber under the trade name Zeofree, and other silicathickening agents.

Advantageously thickening agent are present in the range 0.01 to 30%,preferably 0.1 to 15%.

The thickening agent aspect of this invention is achieved by combining asoluble or sparingly soluble alkali metal pyrophosphate with aninsoluble or essentially insoluble calcium salt and thereby creating insitu material which thickens dentifrices. Useful soluble alkali metalpyrophosphates are, for example, tetrasodium and tetrapotassiumpyrophosphate or combinations thereof. Calcium salts which can be usedin combination with the those pyrophosphates are, for example, CaCO₃,CaHPO₄, and the like. Useful concentrations of the soluble pyrophosphaterange up to about 10.0% of the composition by weight, preferably up to8% by weight. As for the calcium salt, it is expected that some amountin the range of up to 3.0%, preferably 0.5 to 2.6% by weight, willimpart a thickening affect to a dentifrices. If a calcium salt is usedas the abrasive, thickening is achieved without reducing the abrasivecharacteristics of the formulation by increasing the amount of thatabrasive salt by several percentage points, for example 1 to 2%.

Any surfactant may be used in this invention so long as it is notanionic. For example nonionic, cationic and amphoteric surfactants maybe used in these dentifrices.

Suitable nonionic surfactant include polyethoxylated sorbitol monoesters(for instance, the products marketed under the trade name `Tween` byICI); polycondensates of ethylene oxide and propylene oxide (poloxamers)(for instance the products marketed under the trade name `Pluronic` byBASF-Wyandotte); condensates of propylene glycol and polyethoxylatedhydrogenated castor oil (for instance, cremophors).

Suitable amphoteric surfactants include long chain imidazolinederivatives such as the product marketed under the trade name `MiranolC2M` by Miranol; long chain alkyl betaines, such as the product marketedunder the trade name `Empigen BB` by Albright & Wilson; and long chainalkyl amidoalkyl betaines, such as cocamidopropylbetaine, and mixturesthereof.

Useful cationic surfactants may be, for example, cocamidopropyl PGdimonium chloride phosphate (Monaquat PTC) and lauramidopropyl PGdimonium chloride phosphate (Monaquat PTL).

These dentifrices contain abrasives, also called polishing materials.For the purposes of this invention, essentially insoluble abrasives areto be used. The term insoluble is defined with reference to both theconfected dentifrices and its use in the oral cavity.

Examples of such abrasives are certain phosphates such as sodiummetaphosphate, potassium metaphosphate, tricalcium phosphate, dicalciumphosphate dihydrate, anyhdrous dicalcium phosphate, calciumpyrophosphate, zinc orthophosphate, alumina, hydrated alumina, aluminumsilicate, bentonite, certain carbonates such as calcium carbonate, andmixtures thereof. Preferred abrasives include dicalcium phosphate,particularly the dihydrate, calcium pyrophosphate, calcium carbonate andalumina.

Most if not all of the abrasives listed above are available fromcommercial sources, or they can be prepared by means known in the art.For instance, dicalcium phosphate in the preferred dihydrate form isreadily available from many commercial sources. Likewise calciumpyrophosphate and calcium carbonate are commercially available. Ifalumina is used, and there are many sources, it is most preferred to usea hydrated alumina such as that sold by Alcoa as C333. It is understoodthat any chosen abrasive will be sufficiently pure so as to meet thehealth and regulatory standards for a dentifrices.

Abrasives are generally present in amounts ranging from about 5% toabout 95% by weight of the oral preparation. Preferably, they will bepresent in amounts ranging from about 5% to about 75% in toothpaste, andfrom about 10% to about 95% in tooth powder.

In certain forms of this invention a fluoride-providing compound ispresent in the oral preparation. These compounds may be slightly solublein water or may be fully water-soluble. They are characterized by theirability to release fluoride ions in water and by substantial freedomfrom reaction with other compounds of the oral preparation. Among thesematerials are inorganic fluoride salts, such as soluble alkali metal,alkaline earth metal and heavy metal salts, for example, sodiumfluoride, potassium fluoride, ammonium fluoride, lead fluoride, a copperfluoride such as cuprous fluoride, zinc fluoride, a tin fluoride such asstannic fluoride or stannous chlorofluoride, barium fluoride, sodiumfluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, sodiummonofluorophosphate, aluminum mono- and difluorophosphate, andfluorinated sodium calcium pyrophosphate. Alkali metal and tinfluorides, such as sodium and stannous fluorides, sodiummonofluorophosphate and mixtures thereof, are preferred.

The amount of the fluoride-providing compound is dependent to someextent upon the type of compound, its solubility and the type of oralpreparation, but it must be a nontoxic amount. In a solid oralpreparation, such as a toothpaste or tooth powder, an amount of suchcompound which releases a maximum of 1% by weight of the preparation isconsidered satisfactory. Any suitable minimum amount of such compoundmay be used, but it is preferable to employ sufficient compound torelease from 0.005% to 2%, and preferably about 0.1% of fluoride ion.Typically, in the cases of alkali metal fluorides and stannous fluoride,the component is present in an amount up to 4% by weight, based on theweight of the preparation, and preferably in the range of from 0.05% to2%. In the case of sodium monofluorophospate (MFP), the compound may bepresent in an amount up to 7.6% by weight more typically 0.76%.

Optionally, anti-calculus agents may be incorporated into thesecompositions. For example certain pyrophosphates have been found to beuseful in reducing calculus formation. There are numerous publicationsand patents describing pyrophosphate-based anti-calculus compositionsand their use in the oral cavity. For example see U.S. Pat. No.3,515,772 which describes the use of certain alkali metalpyrophosphates, particularly di alkali and tetra-alkali metalpyrophosphate salts of P₂ O₇₋₄. The tetrapotassium and tetrasodium formsare most frequently used in dentifrices as anticalculus agent. This U.S.patent is incorporated herein by reference as if set out in full in thiswriting. Other phosphates, including hexametaphosphates,tripolyphosphates and other polyphosphates, usually in the form of analkali metal salt, have been proposed or are being used in dentifricesas anticalculus agents. It is expected that one or more of these agentscan be usefully incorporated into the compositions of this invention.

In preparing tooth powders, it is usually sufficient to admixmechanically, e.g., by milling, the various solid ingredients inappropriate quantities and particle sizes.

With regard to pastes the liquid vehicle may comprise water, and usuallya humectant, typically in an amount ranging from about 10% to about 90%by weight of the preparation. Glycerin, sorbitol, or polyethylene glycolare examples of useful humectants. Particularly advantageous liquidingredients comprise mixtures of water, glycerine or sorbitol.

Various other ingredients such as preservatives, dyes and other coloringagents, flavorings, sweeteners, anti-staining agents, desensitizingagents and the like may be added to these dentifrices. Such additivesare frequently used in dentifrices and are therefore well known in theart.

It will be understood that these dentifrices are to be sold or otherwisedistributed in suitably labelled packages. Toothpastes are packaged intubes or squeezable tubes (aluminum or plastic) or containers or in arigid tube with some expelling device for delivering the paste, such asa pump. Powders normally are prepared in cans or bottles with aremovable top or some means whereby the powder can be dispensed byinverting and shaking or by introducing a spoon or other device forremoving a portion of the powder. Liquid formulations can be packaged incapped tubes or bottles and be dispensed by squeezing, mechanical means;pre-pressurized containers may also used with liquid formulations.

This invention is further illustrated by the following examples. Theseexamples are only intended to illustrate the invention not to limit itsscope or practice in any manner or form. Formulations are given on aweight/weight basis.

EXAMPLES 1 CPC/Dicalcium Phosphate Abrasive Toothpaste

An example of a toothpaste where the abrasive is dicalcium phosphatedihydrate is set out below. Table I lists the ingredients for the paste,which was tested for the availability of the cationic antibacterial byextracting the water solubles, then looking at the amount of recoveredantibacterial via instrumental analyses such as an HPLC-bases assay andmicrobiological assay.

                  TABLE I                                                         ______________________________________                                                        Percent by                                                    Ingredients     Weight/Weight                                                 ______________________________________                                        Glycerin        7.000                                                         Methocel KI5M.sup.1                                                                           0.600                                                         Na MFP          0.836                                                         Na Saccharin    0.246                                                         Sorbitol        3.550                                                         CaHPO.sub.4 Dihydrate                                                                         40.000                                                        TiO.sub.2       0.956                                                         Flavor          0.800                                                         Deionized Water 36.012                                                        Pluronic F127   9.000                                                         CPC.sup.2       1.000                                                                         100.000                                                       ______________________________________                                         .sup.1 Hydroxymethylpropylcellulose, Dow Chemical Co.                         .sup.2 Cetylpyridinium chloride.                                         

A paste suitable for use as a dentifrice using these materials wasprepared as follows: The glycerin and Methocel were mixed together. Thenthe sodium monofluorophosphate and sodium saccharin were dissolved in aportion of the water and added to the first mix. Sorbitol (Sorbo) wasthen added, followed by a mix of the dicalcium phosphate dihydrate andtitanium dioxide. Flavoring was then added after which a mixture of theremaining water, Pluronics and CPC was mixed into the earlier preparedmixture.

EXAMPLE 2 CPC/Alumina Abrasive Toothpaste

A toothpaste with alumina as the abrasive and CPC as the cationicantibacterial agent was prepared. Table II sets out the ingredients andtheir relative amounts.

                  TABLE II                                                        ______________________________________                                                        Percent by                                                    Ingredients     Weight/Weight                                                 ______________________________________                                        Glycerin        20.000                                                        Natrosol 250 H.sup.3                                                                          1.000                                                         Na MFP          0.836                                                         Na Saccharin    0.246                                                         Alumina         14.000                                                        Zeofree 153.sup.4                                                                             10.000                                                        TiO.sub.2       0.956                                                         PEG 400         3.000                                                         Flavor          0.800                                                         Deionized Water 46.162                                                        Pluronic F-87   1.000                                                         Pluronic F-127  1.000                                                         CPC             1.000                                                                         100.00%                                                       ______________________________________                                         .sup.3 Hydroxyethyl cellulose, Aqualon.                                       .sup.4 Thickening silica, Huber.                                         

The paste was prepared by first combining glycerin and the Natrosol 250Hin a portion of the water. To this was added a mix of water, the sodiummonofluorophosphate and sodium saccharin. Then alumina, Zeofree 153 andtitanium dioxide was combined and added to the existing mixture. A mixof the remaining glycerin and PEG 400 was added followed by theflavoring agent. Finally the rest of the water mixed with the Pluronicsand CPC was added with mixing to form a toothpaste.

EXAMPLE 3 CPC/Alumina Toothpaste with Pyrophosphates

A paste with pyrophosphates for tartar removal was prepared with theCPC/alumina paste of Example 2. Table III recites the ingredients andamounts contained in this preparation.

                  TABLE III                                                       ______________________________________                                                        Percent by                                                    Ingredients     Weight/Weight                                                 ______________________________________                                        Na MFP          0.836                                                         Na Saccharin    0.246                                                         K.sub.4 P.sub.2 O.sub.7                                                                       4.000                                                         Na.sub.2 P.sub.2 O.sub.7                                                                      1.810                                                         Alumina         14.000                                                        Zeofree 153     10.000                                                        TiO.sub.2       0.956                                                         Glycerin        20.000                                                        PEG 400         3.000                                                         Flavor          0.800                                                         Deionized Water 40.352                                                        Pluronic F-127  1.000                                                         Pluronic F-87   1.000                                                         CPC             1.000                                                                         100.000                                                       ______________________________________                                    

A paste was prepared from these materials in the manner described inExample 2.

EXAMPLE 4 CPC/Calcium Pyrophosphate Toothpaste

Toothpastes with calcium pyrophosphate as the abrasive were prepared.Table V gives a representative example of the ingredients which wereused to prepare such pastes.

                  TABLE IV                                                        ______________________________________                                                          Percent by                                                  Ingredients       Weight/Weight                                               ______________________________________                                        K.sub.4 P.sub.2 O.sub.7                                                                         5.000                                                       Na.sub.4 P.sub.2 O.sub.7                                                                        1.810                                                       Na MFP            0.836                                                       Na Saccharin      0.246                                                       CaHPO.sub.4       2.300                                                       Glycerin          22.000                                                      Natrosol 250H     0.600                                                       Calcium pyrophosphate                                                                           40.000                                                      TiO.sub.2         0.956                                                       Flavor            0.800                                                       Pluronic F-127    1.000                                                       Pluronic F-87     1.000                                                       CPC               1.000                                                       Deionized Water   qs 100%                                                     ______________________________________                                    

In making up a paste, a portion of the water was used to dissolve up thepyrophosphates, sodium monofluorophosphate and sodium saccharin. Thenthe dicalcium phosphate was added to that mix. Subsequently, a portionof the glycerin and Natrosol 250H were combined and mixed in withearlier mixture. A mix of calcium pyrophospate and titanium dioxide wasthen prepared and incorporated into the earlier mix. The remainingglycerin was then added, followed by the flavoring agent. Finally, amixture of water, pluronics and CPC was prepared and mixed in with thepreviously described mixture to form the paste.

EXAMPLE 5 CPC/Calcium Carbonate Toothpaste

Toothpastes with calcium carbonate as the abrasive were prepared. TableIV gives a representative example of the ingredients where used toprepare such pastes.

                  TABLE V                                                         ______________________________________                                                        Percent by                                                    Ingredients     Weight/Weight                                                 ______________________________________                                        Natrosol 250 H  1.500                                                         Na MFP          0.836                                                         Na Saccharin    0.246                                                         Zeofree 153     5.000                                                         Glycerin        22.000                                                        CaCO.sub.3      35.000                                                        TiO.sub.2       0.956                                                         Flavor          0.800                                                         Pluronic F-127  1.000                                                         Pluronic F-87   1.000                                                         CPC             1.000                                                         Deionized Water qs 100%                                                       ______________________________________                                    

Here, qs refers to a quantity sufficient to make 100%. The order ofmixing was as follows: Part of the glycerin, part of the water andNatrosol 250H were combined. To this was added a mixture comprisingwater, sodium monofluorophosphate and sodium saccharin. Calciumcarbonate was added to this mixture. The remaining glycerin was thenadded followed by a mixture of the Zeofree and the titanium dioxide.Flavoring was added following by a mix of the Pluronics and CPC.

What is claimed is:
 1. A dentifrice for reducing plaque formation andtreating gingivitis on teeth and soft tissue which has a pH between 6and 8 consisting essentially of:(a) a cationic quaternary ammoniumantibacterial agent in an amount between about 0.005 and 10% by weight;(b) at least one thickening agent which is not an anionic thickeningagent; (c) at least one surfactant which is not an anionic surfactant;and (d) and an abrasive consisting essentially of a compound selectedfrom the group consisting of calcium carbonate, dicalcium phosphate andcalcium pyrophosphate.
 2. The dentifrice of claim 1 where the abrasiveis dicalcium phosphate dihydrate which is present in an amount betweenabout 5% to about 75% w/w.
 3. The dentrifice of claim 2 where thequaternary ammonium compound is present in a toothpaste in an amountbetween about 0.005 to 5% (w/w).
 4. The dentifrice of claim 3 where thequaternary ammonium compound is cetylpyridinium chloride.
 5. Thedentrifice of claim 4 where the dicalcium phosphate dihydrate is presentin about 40% and the cetylpyridinium chloride in about 1.0% and alsocontains a fluoride-providing compound and an anticalculus agent.